Complexity-based dynamical analysis of a network

ABSTRACT

In a subject undergoing therapeutic intervention, efficacy of the therapeutic intervention is assessed based on a series of physiologic data associated with the subject. The series of physiologic data is analyzed to produce a measure of complexity. The complexity measure is then compared to a control. The efficacy of the therapeutic intervention is assessed based on the comparison of the complexity measure to the control. The control may be, for example, a complexity measure taken prior to initiation of the therapeutic intervention, a complexity measure taken from a different subject, or a predetermined threshold value. The measure of complexity is generated using, for example, a multiscale entropy measurement (MSE), a time asymmetry measurement, and/or an information-based similarity measurement. An increase in complexity indicates a positive effect of the therapeutic intervention, while a decrease in complexity indicates a negative effect of the therapeutic intervention. Stability of a non-biologic network, such as a computer network, communications network or transportation network can also be assessed.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.11/356,044, filed Feb. 17, 2006, which claims priority to U.S.Provisional Appl. No. 60/654,079, filed Feb. 18, 2005, both of which areincorporated herein by reference.

STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH AND DEVELOPMENT

Part of the work performed during development of this invention utilizedU.S. Government funds. The U.S. Government has certain rights in thisinvention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to analyzing time series data,and more specifically, to non-invasively assessing therapeutic toxicityand efficacy from physiologic measurements.

2. Related Art

The physiologic systems of a living organism generate complexfluctuations in their output signals. The complex fluctuations (alsoreferred to as “complexity”) arise from the interaction of a myriad ofstructural units and regulatory feedback loops that operate over a widerange of temporal and spatial scales. This interaction reflects theorganism's ability to adapt to the stress of everyday life.

Being able to quantify or model physiologic complexity would provideinsight into the underlying dynamics of an organism. For example, adecrease in physiologic complexity can be symptomatic of a pathologicprocess. However, contemporary mathematical approaches to measuring thecomplexity of biological signals fail to account for the multiple timescales inherent in such time series. These approaches have yieldedcontradictory findings when applied to real-world datasets obtained inhealth and disease states.

Conventional biomedical approaches to designing therapeuticinterventions for pathologic processes are also plagued with severalshortcomings. Current screening tests and assays for the efficacy andtoxicity of pharmacologic and non-pharmacologic interventions are basedprimarily on local effects and on the measurement of a limited range ofmarkers. Such measures fail to account for systemic effects associatedwith integrative feedback (also referred to as a “systems biologyapproach”). Thus, a drug might appear to have beneficial effects in theshort-term, or based on site-specific actions. However, more sustaineduse might be associated with lethal toxicities not detected in theconventional evaluation. The literature is replete with examples of suchunexpected toxicities, including the notorious examples of cardiac“antiarrhythmic” drugs that have “proarrhythmic” effects and increasethe risk of sudden cardiac arrest.

A fundamental problem in the development of novel therapeutic agents andthe ongoing monitoring of approved drugs, as well as non-pharmacologicinterventions, is the sensitive assessment of their systemic safety andefficacy. Current methodologies for evaluating both efficacy andtoxicity, however, largely fail to account for the effects onintegrative physiologic function.

Therefore, a need exists to develop a technology that can overcome theaforementioned limitations and provide a more efficient andcost-effective technique and/or methodology for evaluating complexityand/or therapeutic interventions.

SUMMARY OF THE INVENTION

The present invention includes a method, system and computer programproduct for assessing system complexity via a panel of measurements.According to embodiments of the present invention, these measurementsare used to detect aging, pathology, toxicity, and/or efficacy oftherapeutic intervention, or the like.

In an embodiment, a panel of dynamical measurements quantifies differentaspects of physiologic complexity and information content. The panelincludes, but is not limited to, multiscale entropy (MSE), timeasymmetry, and information-based similarity metrics.

In an embodiment, a series of physiologic data is accessed fromnon-invasive and/or invasive measurements that are taken from a subject.One or more of the measurements from the panel are used to quantify thesystem's complexity and its information content by examination of thephysiologic time series. The computed complexity-based measurement(s)are compared to a threshold parameter(s) and/or a template curve ofcomplexity values over multiple scales. If the threshold parameter(s)and/or the values of the template curve exceed the computedmeasurements, a loss of complexity is detected. Otherwise, no loss ofcomplexity is detected, or a gain in complexity is detected if thecomputed complexity measurement(s) exceed the threshold parameter(s).

In an embodiment, a loss of complexity is associated with aging or apathological condition. A gain in complexity is associated with animprovement from a pathological condition.

In an embodiment, one or more measurements from the panel can be appliedto quantify the effects of drug and non-pharmacologic intervention. Assuch, interventions that enhance system complexity are associated withtherapeutic effects, and interventions that degrade system complexityare associated with adverse effects.

One type of measurement for quantifying physiologic complexity andinformation content is the MSE approach. MSE approach can be applied toinvestigate the degree of complexity in physiologic signals and othertime series that have correlations at multiple spatial and temporalscales. The results of the MSE approach can be applied to differentiatetime series which are the output of different dynamical systems or arerepresentative of different states of the same system. In particular,the MSE method can be applied to discriminate time series obtained fromhealthy and unhealthy subjects, younger and elderly subjects,1-over-frequency (1/f) noise and white noise time series, etc.

In an embodiment, physiologic time series data is gathered from asubject. The time series data is processed to compute multiplecoarse-grained time series. An entropy measure (e.g., sample entropy) iscalculated for each coarse-grained time series plotted as a function ofthe scale factor. The plotted function is herein referred to as an MSEcurve. In order to determine whether the complexity of the system hasincreased, decreased, or remained constant, the plotted MSE curve iscompared to a template curve, which, according to the aims of thespecific study, can be: (i) the curve obtained from the MSE analysis ofa representative group of healthy subjects connecting the mean entropyvalues for each scale; or (ii) the MSE curve for a time series obtainedfrom the subject being studied in an earlier state of the disease orprior to the initiation of drug or other non-pharmacologic therapy. Thetwo MSE curves are compared according to the following rules: (i) if forthe majority of scales, the values of entropy are higher for time seriesa than b, then time series a is more complex than time series b; and(ii) a monotonic decrease of the values of entropy indicates that thestructure of the time series is similar to that of uncorrelated randomnoise time series which are the least complex of all.

In an embodiment, the MSE approach is applied to the cardiac interbeatinterval time series of healthy subjects, those with congestive heartfailure (CHF), and those with atrial fibrillation (AF). The MSE approachshows that healthy dynamics are the most complex. Under pathologicconditions, the structure of the time series' variability may change intwo different ways. One dynamical route to disease is associated withloss of variability and the emergence of more regular patterns (e.g.,heart failure). The other dynamical route is associated with more randomtypes of outputs (e.g., atrial fibrillation). In both cases, a decreasein system complexity occurs under pathologic conditions.

When applied to simulated time series, the MSE approach reveals thatcorrelated random signals (e.g., 1/f noise time series) are more complexthan uncorrelated random signals (e.g., white noise time series). Theseresults are consistent with the presence of long-range correlations in1/f noise time series but not in white noise time series.

In an embodiment, the MSE approach is applied to compare the complexityof an executable computer program versus a compressed non-executablecomputer data file, and the complexity of selected coding versusnon-coding DNA sequences. The MSE approach reveals that the executablecomputer program has higher complexity than the non-executable computerdata file. Similarly, the MSE approach reveals that the non-codingsequences are more complex than the coding sequences examined. As such,the present invention supports recent in vitro and in vivo studiessuggesting, contrary to the “junk DNA” theory, that non-coding sequencescontain important biological information.

A second type of measurement useful to compare different time series isthe time asymmetry approach. The time asymmetry approach can be appliedto physiologic signals and other time series to produce a measure thatquantifies the degree of temporal irreversibility of a signal overmultiple spatial and/or temporal scales. In an embodiment, a physiologictime series X={x₁, x₂, . . . , x_(N)} gathered from a subject isprocessed to compute multiple coarse-grained time series according tothe equation y_(τ)(i)=(x_(τ+i)−x_(i))/τ with i≦N−τ. Next, the histogramfor each coarse-grained time series is calculated. For the study ofheart rate time series, the inverse of the electrocardiographic Holterrecording sample frequency is used as the histogram's bin size, denotedas Δ. Of note, the histogram is a function H(n) that associates thenumber of data points between nΔ and (n+1)Δ to each nεN. In anembodiment, a measure of the degree of irreversibility of eachcoarse-grained time series is calculated according to the equation:

${\hat{A}(\tau)} = \frac{{\sum\limits_{n > 0}{{H(n)} \times {\ln\left\lbrack {H(n)} \right\rbrack}}} - {{H\left( {- n} \right)} \times {\ln\left\lbrack {H\left( {- n} \right)} \right\rbrack}}}{\sum\limits_{n \neq 0}{{H(n)} \times {\ln\left\lbrack {H(n)} \right\rbrack}}}$

The multiscale asymmetry index (A_(I)) is computed from the followingequation:

$A_{I} = {\sum\limits_{\tau = 1}^{L}{{\hat{A}(\tau)}.}}$

In embodiments, the computed A_(I) is compared to a threshold A_(I) todetermine an increase, decrease, or consistency in physiologiccomplexity.

A third type of measurement for quantifying physiologic complexity andinformation content is the information-based complexity approach. Theinformation-based similarity approach is based on rank order statisticsof symbolic sequences to investigate the profile of different types ofphysiologic dynamics. This approach can be applied to physiologicsignals and other series to produce a measure that incorporatesinformation from multiple spatial and temporal scales. In an embodiment,a time series of physiologic data gathered from a subject is compared toa time series of a prototypically healthy subject. Each physiologic timeseries is mapped to a binary time series. In the case of the cardiacinterbeat interval time series, each pair of consecutive interbeatintervals is mapped to the symbols 0 or 1 depending on whether thedifference between the two intervals is ≦0 or <0. In an embodiment, anm-bit word is defined as sequences of m consecutive symbols. Each m-bitword represents a unique pattern of fluctuations in the time series. Byshifting one data point at a time, a collection of m-bit words areproduced over the whole time series. Next, the occurrences of differentwords are counted and, the different words are sorted according todescending frequency. After a rank-frequency distribution has beenproduced for both time series, a measurement of similarity between thetwo signals is defined by plotting the rank number of each m-bit word inthe first time series against that of the second time series. Theaverage deviation of these scattered points away from a diagonal line isa measure of the “distance” between these two time series. Greaterdistance indicates less similarity and less complexity, and lessdistance indicates greater similarity and greater complexity.

Thus, in an embodiment, the similarity measurement is applied toquantify physiologic complexity. For example, two time series obtainedbefore and after an intervention are compared to a time series of aprototypically healthy subject. If the distance between the time seriesof a prototypically healthy subject and the time series of a subjectobtained before a pharmacologic or non-pharmacologic intervention islarger than the distance between the time series of a prototypicallyhealthy subject and the time series obtained after the intervention,then the effect of the intervention is a decrease in the system'scomplexity. If the distance between the time series of a prototypicallyhealthy subject and the time series of a subject obtained before apharmacologic or non-pharmacologic intervention is smaller than thedistance between the time series of a prototypically healthy subject andthe time series obtained after the intervention, then the effect of theintervention is an increase in the system's complexity. Finally, ifthere is no difference between the distances calculated before and afterthe intervention, then the intervention does not change the complexityof the system.

In another embodiment, the invention is used to assess the stability ofthe output of non-biologic networks. For example, the invention can beused to assess the stability of the output of the global Internet, awide area network (WAN), a local area network (LAN), a Web server, othertelecommunications networks, electricity flow in a power grid, as wellas systems for managing air traffic flow, automotive traffic flow,shipping traffic in busy sea ports, rail traffic flow, and the like. Insuch environments, a loss of complexity in the output of the system maybe a marker of a breakdown of network stability and possibly on animpending catastrophic failure.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

The accompanying drawings, which are incorporated herein and form partof the specification, illustrate the present invention and, togetherwith the description, further serve to explain the principles of theinvention and to enable one skilled in the pertinent art(s) to make anduse the invention. In the drawings, generally, like reference numbersindicate identical or functionally or structurally similar elements.Additionally, generally, the leftmost digit(s) of a reference numberidentifies the drawing in which the reference number first appears.

FIG. 1 illustrates a multi-panel approach for measuring complexity andinformation content from a subject.

FIG. 2 illustrates quantifying physiologic complexity from MSEmeasurements.

FIG. 3 illustrates coarse-graining a data series for scales 2 and 3.

FIG. 4 illustrates a calculation of sample entropy.

FIG. 5 illustrates a cardiac interbeat interval time series from healthyand unhealthy subjects.

FIG. 6 illustrates an MSE analysis of interbeat interval time seriesobtained from 72 healthy subjects, 43 patients with heart failure and 9subjects with atrial fibrillation. Symbols represent mean values ofsample entropy and error bars represent standard errors.

FIG. 7 illustrates the slopes of the MSE curves for small and large timescales obtained from the group of subjects analyzed in FIG. 6.

FIGS. 8A and 8B illustrate MSE results for the interbeat interval timeseries obtained before (PRE) and after (POST) treatment onset with thecardiac antiarrhythmic drug encainide. FIG. 8A presents MSE curves forthe time series obtained from one representative subject. FIG. 8Bpresents complexity indexes C_(I) for a randomly selected subset of theNIH Cardiac Arrhythmia Suppression Trial RR Interval Sub-Study Databasecomprising ten subjects treated with encainide. The NIH CardiacArrhythmia Suppression Trial RR Interval Sub-Study Database is availableat http://www.physionet.org/physiobank/database/crisdb/. Solid lineswere used when complexity decreased after treatment onset. Dotted lineswere used when complexity increased after treatment onset.

FIGS. 9A and 9B illustrate MSE results for the interbeat interval timeseries obtained before (PRE) and after (POST) treatment onset with thecardiac antiarrhythmic drug flecainide. FIG. 9A presents the MSE curvesfor the time series obtained from one representative subject. FIG. 9Bpresents complexity indexes C_(I) for a randomly selected subset of theNIH Cardiac Arrhythmia Suppression Trial RR Interval Sub-Study Databasecomprising ten subjects treated with flecainide. Solid lines were usedwhen complexity decreased after treatment onset. Dotted lines were usedwhen complexity increased after treatment onset.

FIGS. 10A and 10B illustrate MSE results for the interbeat interval timeseries obtained before (PRE) and after (POST) treatment onset with thecardiac antiarrhythmic drug moricizine. FIG. 10A presents MSE curves forthe time series obtained from one representative subject. FIG. 10Bpresents complexity indexes C_(I) for a randomly selected subset of theNIH Cardiac Arrhythmia Suppression Trial RR Interval Sub-Study Databasecomprising ten subjects treated with moricizine. Solid lines were usedwhen complexity decreased after treatment onset. Dotted lines were usedwhen complexity increased after treatment onset.

FIGS. 11A and 11B show MSE results for the center of pressure sway timeseries of young (FIG. 11A) and elderly (FIG. 11B) subjects before andduring the application of subsensory noise to the sole of the feet.

FIG. 12 illustrates the probability of distinguishing two randomlychosen data points from a coarse-grained time series of a binarydiscrete time series.

FIG. 13 illustrates an MSE analysis of binary time series derived fromcomputer executable and computer data files.

FIG. 14 illustrates an MSE analysis of human coding and noncoding DNAsequences.

FIG. 15 illustrates a method for quantifying physiologic complexity fromtime asymmetry measurements.

FIGS. 16A-16E illustrate a multiscale time asymmetry analysis ofinterbeat interval time series from representative subjects including:healthy young subjects (FIG. 16A); healthy elderly subjects (FIG. 16B);subjects with congestive heart failure (FIG. 16C); and subjects withatrial fibrillation (FIG. 16D). FIG. 16E shows the asymmetry index for agroup of 26 healthy young subjects, 46 healthy elderly subjects, 43congestive heart failure subjects and 9 subjects with atrialfibrillation.

FIG. 17 illustrates a method for quantifying physiologic complexity frominformation-based similarity measurements.

FIG. 18 illustrates a mapping procedure for 8-bit words from a timeseries.

FIG. 19 illustrates a probability distribution of every 8-bit word fromthe time series analyzed in FIG. 23.

FIG. 20 illustrates a rank ordered probability plotted on a log-logscale.

FIG. 21 illustrates a rank order comparison of two cardiac interbeatinterval time series from the same subject.

FIG. 22 illustrates a rooted phylogenic tree generated between five testgroups.

FIG. 23 illustrates a heartbeat interval time series from a healthysubject.

FIG. 24 illustrates a heartbeat interval time series from a subject withcongestive heart failure.

FIG. 25 illustrates a rank order comparison of the time series of FIG.23 and its randomized surrogate.

FIG. 26 illustrates a rank order comparison of the time series of FIG.24 and its randomized surrogate.

FIG. 27 illustrates nonrandomness index values of the interbeat intervaltime series derived from four subject groups.

FIG. 28 illustrates an example computer system useful for implementingportions of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

According to embodiments of the present invention, a method, system, andcomputer program product are provided to perform a quantitative analysisof the degree of physiologic complexity of an organism. Physiologiccomplexity is associated with the ability of living systems to adjust toan ever-changing environment, which requires integrative multiscalefunctionality. Under free-running conditions, a sustained decrease incomplexity reflects a reduced ability of the system to function incertain dynamical regimes possibly due to decoupling or degradation ofcontrol mechanisms. Thus, physiologic complexity is a generic feature ofpathologic dynamics. As such, a loss of complexity or informationcontent is a fundamental and consistent marker of adverse effects(including pathology and age-related degenerative changes), and anincrease in complexity indicates a potentially therapeutic or healthfuleffect.

In an embodiment, a panel of dynamical measurements quantifies differentaspects of physiologic complexity and information content. The panelincludes, but is not limited to, multiscale entropy (MSE), timeasymmetry, and information-based similarity metrics. Each of thesemeasurements is described in greater detail below.

By adapting methodologies from nonlinear dynamics and complexityscience, the panel produces complexity and complexity relatedmeasurements based on analyses of variables that reflect systemdynamics, such as cardiac interbeat interval dynamics that are readilyobtained by a surface electrocardiogram. In an embodiment, the panel ofdynamical measurements provides a systematic way of measuring theeffects of pharmacologic and non-pharmacologic therapies and relatedinterventions on integrated, multiscale system function. The panelprovides a means for assessing efficacy and providing an early warningabout potential toxicity that is not otherwise detectable byconventional assays. As discussed above, conventional assays forevaluating efficacy and toxicity fail to account for the effects onintegrative physiologic function. The panel of the present inventionquantifies the effects of drugs on the overall complexity of aphysiologic system, and therefore is effective for monitoring andscreening drug and non-pharmacologic intervention effects based onanalysis of variables that reflect system dynamics.

Referring to FIG. 1, flowchart 100 represents the general operationalflow of an embodiment of the present invention. More specifically,flowchart 100 shows an example of a control flow for measuringcomplexity and information content of a physiologic signal or ofphysiologic data from a subject (such as, a patient, test/laboratorysubject, or the like) using multiscale entropy (MSE) measurements ortime asymmetry measurements.

The control flow of flowchart 100 begins at step 101 and passesimmediately to step 103. At step 103, a series of physiologic data isgathered from a monitoring system. For example, data can be taken from atwenty-four hour continuous electrocardiographic (ECG) Holter monitorrecording of a subject. The ECG data is used to derive a cardiacinterbeat (RR) interval time series. In another embodiment, an RRinterval time series is acquired from another type of physiologic signalrepresenting heart rate dynamics within a subject. Thus, the heart ratephysiologic signal can be derived from, for example, ECG, bloodpressure, pulse Doppler flow (e.g., sensed via ultrasound recording),ECG signal from another electrical signal (e.g., electroencephalographic(EEG)), or the like.

In another embodiment, other types of non-invasive and invasivemeasurements can be used in conjunction with or in lieu of a heart ratephysiologic data. For example, the physiologic data can include arespiratory signal, an electroencephalographic (EEG) signal, aneuromuscular signal, or the like.

At step 106, the ECG and/or other non-invasive or invasive measurementsare processed to quantify the system's complexity and informationcontent. In an embodiment, a panel of complexity-based measurements isapplied to quantify the system complexity and information content. Inthis embodiment, the panel includes, but is not limited to, MSE and timeasymmetry measurements. To quantity the complexity, one or more of thepanel measurements are applied. Each of these measurements is describedin greater detail below.

At step 109, the computed complexity-based measurement(s) are comparedto a threshold parameter(s). The threshold parameter(s) represent basevalues or values computed from a normal or healthy subject. Thethreshold parameter(s) are described in greater detail below.

If the threshold parameter(s) exceed the computed measurement(s),control passes to step 112, and loss of complexity is detected.Otherwise, control passes to step 115, and no loss of complexity isdetected. A gain in complexity is determined if the computedmeasurement(s) exceed the threshold parameter(s). Afterwards, thecontrol flow ends as indicated at step 195.

As discussed, the present invention can be used to quantity the effectsof drug and non-pharmacologic intervention. As such, interventions thatenhance system complexity (as detected at step 115) are associated withtherapeutic effects, and those interventions that degrade systemcomplexity (as detected at step 112) are associated with adverseeffects.

Accordingly, the present invention can be used in preclinical animal andPhase 1-3 clinical design, development and testing of pharmacologicagents to help assess therapeutic efficacy and toxicity. The presentinvention can also be used in high throughput testing of drugs and othernon-pharmacologic interventions to screen for new agents with salutaryintegrated physiologic effects that might not be detected byconventional screening. The present invention can also be used to assessapproved pharmacologic agents and other non-pharmacologic interventionsto detect potential toxicities not identified in animal and Phase 1-3trials by the United States Food and Drug Administration (FDA) or othergovernmental agencies.

The approach has been tested on three pharmacologic agents, namelyencainide, flecainide and moricizine, using data from a subsetcomprising 30 subjects of an open-access database from the historicCardiac Arrhythmia Suppression Trial (CAST) study. This database isavailable at the website:http://www.physionet.org/physiobank/database/crisdb/. These threecardiac antiarrhythmic agents were shown, unexpectedly in the originaltrial, to increase mortality. Re-analysis of the pre- and post-drugHolter monitor data from this study using complexity-based measurementsof the present invention identifies a loss of complexity in heart ratedynamics after administration for all three agents, thereby providingdirect evidence for increased risk of adverse future outcomes. Thefinding of a loss of system complexity with any drug is a major “redflag” since it suggests loss of system adaptability and functionality.The present invention provides a way to screen new cardiacantiarrhythmic agents (and, indeed all other drugs) for such “hidden”toxicity.

Multiscale Entropy (MSE) Analysis of Physiologic Signals

As discussed, the present invention provides a panel of dynamicalmeasurements that quantifies different aspects of physiologic complexityand information content. In one embodiment, the panel of dynamicalmeasurements includes, but is not limited to, MSE measurements and timeasymmetry measurements. The first methodology, the MSE approach, iseffective for investigating complexity in physiologic signals and otherseries that have correlations at multiple time scales. As describedherein, the MSE approach is utilized to characterize the fluctuations ofa human heartbeat under physiologic and pathologic conditions. However,other types of physiologic data series can be used, including but notlimited to, respiratory signals, brain waves, or the like.

Conventional methods quantify the degree of regularity of a time serieson a single scale by evaluating the appearance of repetitive patterns.However, there is no straightforward correspondence between regularity,which can be measured by entropy-based algorithms, and complexity.Intuitively, complexity is associated with “meaningful structuralrichness,” which, in contrast to the outputs of random phenomena,exhibits relatively higher regularity. (See P. Grassberger inInformation Dynamics, edited by H. Atmanspacher et al., p 15, PlenumPress, NY, 1991, which is incorporated herein by reference).Entropy-based measures, such as the entropy rate and the Kolmogorovcomplexity, grow monotonically with the degree of randomness. Therefore,these measures assign the highest values to uncorrelated random signals(i.e., white noise), which are highly unpredictable but not structurally“complex,” and, at a global level, admit a very simple description.

The MSE approach integrates information about the degree of irregularityof a time series in multiple scales. The MSE approach is based on thehypothesis that the outputs of more complex dynamical systems likelypresent structures with higher information content in multiple scalesthan those from less complex systems. The MSE method consistentlyreveals that correlated random signals (e.g., 1/f noise time series) aremore complex than uncorrelated random signals (e.g., white noise timeseries). These results are consistent with the presence of long-rangecorrelations in 1/f noise time series but not in white noise timeseries. In contrast, the analysis of the same time series with singlescale-based entropy algorithms may lead to misleading results as higherentropy values are assigned to white noise than to 1/f noise timeseries.

When applied to physiologic time series, conventional entropy-basedalgorithms can lead also to misleading results. For example, they assignhigher entropy values to certain pathologic cardiac rhythms thatgenerate erratic outputs than to healthy cardiac rhythms that areexquisitely regulated by multiple interacting control mechanisms.

The present invention addresses this longstanding problem and ispredicated on the following hypotheses: i) the complexity of abiological system reflects its ability to adapt and function in anever-changing environment; ii) biological systems need to operate acrossmultiple spatial and temporal scales, and hence their complexity is alsomulti-scaled; and iii) a wide class of disease states as well as agingwhich reduce the adaptive capacity of the individual, appear to degradethe information carried by output variables. Thus, a loss of complexityis a generic feature of pathologic dynamics. Accordingly, the MSEapproach of the present invention computes a complexity measurement thatfocuses on quantifying the information expressed by the physiologicdynamics over multiple spatial and temporal scales.

Due to the interrelationship of entropy and scale, which is incorporatedin the MSE approach, the results are consistent with the considerationthat both completely ordered and completely random signals are notreally complex. Compared to conventional complexity measures, the MSEapproach has the advantage of being applicable to both physiologic andphysical signals of finite length.

Referring to FIG. 2, flowchart 200 represents the general operationalflow of an embodiment of the present invention. More specifically,flowchart 200 shows an example of a control flow for quantifyingphysiologic complexity from MSE measurements.

The control flow of flowchart 200 begins at step 201 and passesimmediately to step 203. At step 203, a series of physiologic data isgathered from non-invasive and/or invasive measurements taken from asubject. For example, data can be taken from a twenty-four hourcontinuous ECG Holter monitor recording, and used to derive an RRinterval time series.

At step 206, the physiologic time series data is processed to computemultiple coarse-grained time series. For instance, given aone-dimensional discrete time series {x₁, . . . , x_(i), . . . , x_(N)}that represents the physiologic time series data, consecutivecoarse-grained time series {y^((τ))} can be constructed that correspondsto the scale factor τ. To compute the coarse-grained time series, theoriginal time series is divided into non-overlapping windows of lengthτ, and the data points inside each window are averaged. In anembodiment, each element of the coarse-grained time series is calculatedaccording to the equation:

${y_{j}^{(\tau)} = {\frac{1}{\tau}{\sum\limits_{i = {{{({j - 1})}\tau} = 1}}^{j\;\tau}x_{i}}}},{1 \leq j \leq {N\text{/}\tau}}$

The length of each coarse-grained time series is equal to the length ofthe original time series divided by the scale factor τ. For scale one,the time series {y⁽¹⁾} is simply the original time series, or N/τ.Similarly, the length of the time series is N/2 for scale 2, the lengthis N/3 for scale 3, and so forth. FIG. 3 illustrates the coarse-grainingprocess for scales 2 and 3, according to an embodiment of the presentinvention.

At step 209, the sample entropy statistic is used to calculate entropyfor each coarse-grained time series plotted as a function of the scalefactor τ. The plotted function is herein referred to as an MSE curve.

At step 212, the plotted MSE curve is compared to a template MSE curverepresentative of a normal or healthy subject or of the subject beingstudied before the initiation of the therapy or in an earlier state ofthe disease.

If, for a given range of scales, the values of the entropy and/or ofparameters derived from the template MSE curve are higher than thosefrom the plotted MSE curve, control passes to step 215, and loss ofcomplexity is detected for all scales within that range. Otherwise,control passes to step 218. If, for a given range of scales, the valuesof the entropy and/or of parameters derived from the computed MSE curveare higher than those from the template MSE curve, an increase incomplexity is determined.

A monotonic decrease of the entropy values indicates that the originalsignal contains information only in the smallest scale, in which casethe time series has very low complexity. Afterwards, the control flowends as indicated at step 295.

In the discussion above of steps 209 and 212, an MSE curve is plottedand compared to a template MSE curve. While curve plotting provides avisual mechanism for comparing data and observing similarities and/ordifferences in the underlying data, a person skilled in the art willrecognize that such plotting is optional. For example, in an alternateembodiment, a computer can be used to compare the MSE data withoutrequiring plotting.

As discussed above, the MSE approach can be used to quantify the effectsof drug and non-pharmacologic intervention. As such, interventions thatenhance system complexity (as detected at step 218) are associated withtherapeutic effects, and those interventions that degrade systemcomplexity (as detected at step 215) are associated with adverseeffects.

As discussed above, entropy values defining the MSE curves arecalculated using an entropy statistic called sample entropy (see Richmanet al. Am. J. Physiol. 2000, 278: J239-H249, which is incorporatedherein by reference), according to the equation:

${{SE}\left( {m,r,N} \right)} = {\ln\frac{\sum\limits_{i = 1}^{N - m}n_{i}^{m}}{\sum\limits_{i = 1}^{N - m}n_{i}^{m + 1}}}$

Sample entropy is equal to the negative of the natural logarithm of theconditional probability that sequences close to each other for “m”consecutive data points would also be close to each other when one morepoint is added to each sequence. FIG. 4 illustrates the calculation ofsample entropy, according to an embodiment of the present invention. Asimulated time series u[1], . . . , u[N] is shown to illustrate theprocedure for calculating sample entropy for the case in which thepattern length “m” is 2, and “r” is a given positive real value.Typically, r is a given positive real value that is chosen to be between10% and 20% of the sample deviation of the time series. Dottedhorizontal lines around data points u[1], u[2] and u[3] representu[1]±r, u[2]±r, and u[3]±r, respectively. Two data values match eachother, that is, they are indistinguishable, if the absolute differencebetween them is ≦r. The symbol “o” is used to represent data points thatmatch the data point u[1]. Similarly, the symbols “x” and “Δ” are usedto represent data points u[2] and u[3], respectively.

Consider the 2-component “o-x” template sequence (u[1], u[2]) and the3-component “o-x-Δ” (u[1], u[2], u[3]) template sequence. For thesegment shown in FIG. 4, there are two “o-x” sequences, (u[13], u[14])and (u[43], u[44]), that match the template sequence (u[1], u[2]) butonly one “o-x-Δ” sequence that matches the template sequence (u[1],u[2], u[3]). Therefore, in this case, the number of sequences matchingthe 2-component template sequences is two and the number of sequencesmatching the 3-component template sequence is one. These calculationsare repeated for the next 2-component and 3-component template sequence,which are, (u[2], u[3]) and (u[2], u[3], u[4]), respectively. Thenumbers of sequences that match each of the 2-component and 3-componenttemplate sequences are again counted and added to the previous values.This procedure is then repeated for all other possible templatesequences, (u[3], u[4], u[5]), . . . , (u[N−2], u[N−1], u[N]), todetermine the ratio between the total number of 2-component templatematches and the total number of 3-component template matches. The sampleentropy, therefore, is the natural logarithm of this ratio and reflectsthe probability that sequences that match each other for the first twodata points will also match for the next point.

The MSE approach of the present invention has been tested on cardiacinterbeat (RR) interval time series derived from twenty-four hourcontinuous ECG Holter monitor recordings of (a) healthy subjects, (b)subjects with congestive heart failure (a life-threatening condition),and (c) subjects with atrial fibrillation (a major cardiac arrhythmia).This data is available at http://physionet.org.

The data for the normal control group were obtained from a twenty-fourhour Holter monitor recordings of seventy-two healthy subjects(including thirty-five men and thirty-seven women, aged 54.6±16.2 years(mean±SD), range 20-78 years). ECG data were sampled at 128 Hz.

The data for the congestive heart failure group were obtained fromtwenty-four hour Holter monitor recordings of forty-three subjects(including twenty-eight men and fifteen women, aged 55.5±11.4 years(mean±SD), range 22-78 years). New York Heart Association (NYHA)functional classification is provided for each subject: 4 subjects wereassigned to class I, 8 to class II, 17 to class III and 14 to classIII-IV. Fourteen recordings were sampled at 250 Hz, and twenty-ninerecordings were sampled at 128 Hz.

The data for the atrial fibrillation group were obtained from ten hourHolter monitor recordings sampled at 250 Hz of nine subjects. Datasetswere filtered to exclude artifacts, premature ventricular complexes, andmissed beat detections. Of note, the inclusion of the prematureventricular complexes does not qualitatively change the MSE analysis.

FIG. 5 shows representative time series of healthy subjects (top panel),subjects with congestive heart failure (middle panel), and subjects withatrial fibrillation (lower panel). When discussing the MSE results ofcardiac interbeat interval time series, reference to “large” and “small”time scales are made when the scales are larger or smaller,respectively, than one typical respiratory cycle length, that is, forexample, approximately five cardiac beats.

In FIG. 6, the results of an MSE analysis are presented for the RRinterval time series for the three groups of subjects. Three differenttypes of behaviors can be observed. First, the entropy measure for thetime series derived from healthy subjects increases on small timescales, and then stabilizes to a relatively constant value. Second, theentropy measure for the time series derived from subjects withcongestive heart failure markedly decreases on small time scales, andthen gradually increases. Third, the entropy measure for the time seriesderived from subjects with atrial fibrillation monotonically decreases,similar to white noise.

For scale one, which is the only scale considered by conventionalsingle-scale based methods, the entropy assigned to the heartbeat timeseries of subjects with atrial fibrillation and those with congestiveheart failure is higher than the entropy assigned to the time series ofhealthy subjects. In contrast, for sufficiently large scales, the timeseries of healthy subjects are assigned the highest entropy values.Thus, the MSE approach indicates that healthy dynamics are the mostcomplex, contradicting the results obtained using the conventionalentropy algorithms.

The time series of subjects with atrial fibrillation exhibit substantialvariability in beat-to-beat fluctuations. However, the monotonicdecrease of the entropy with scale reflects the degradation of thecontrol mechanisms regulating heart rate on larger time scales in thispathologic state.

The asymptotic value of entropy may not be sufficient to differentiatetime series that represent the output of different dynamical processes.Referring back to FIG. 6, for time scale 20, the values of the entropymeasure for the heart failure (sinus rhythm) and atrial fibrillationtime series are the same. However, these time series represent theoutput of very different types of cardiac dynamics. Therefore, not onlythe specific values of the entropy measure but also their dependence ontime scale need to be taken into account to better characterize thephysiologic process.

In FIG. 7, two features of the MSE curves, shown in FIG. 6, areextracted. The features are the slopes for small and large time scales(i.e., the slopes of the curves defined by the sample entropy valuesbetween scale factors 1 and 5, and scale factors 6 and 20,respectively). As can be seen, there is a notable separation between thetwo groups. Considering other features of the MSE curves, in addition tothese slopes, may further improve the separation. Alternatively methodsderived from pattern recognition techniques (e.g. Fisher's discriminant)may also be useful for clinical discrimination.

Note that the cardiac analyses reported herein pertain to interbeatinterval dynamics under free-running conditions. The high capability ofhealthy systems to adapt to a wide range of perturbations requiresfunctioning in a multidimensional state space. However, under stress,the system is forced to work in a tighter regime. For example, duringphysical exercise, there is a sustained increase in heart rate and adecrease in the amplitude of the interbeat interval fluctuations inresponse to an increased demand for oxygen and nutrients. The dynamicsare, therefore, limited to a subset of the state space. It isanticipated that under a variety of stressed conditions, healthy systemswill generate less complex outputs than under free-running conditions.

FIGS. 8-11 present the MSE results of the analysis of the RR intervaltime series from a randomly selected subset of the NIH CardiacArrhythmia Suppression Trial (CAST) RR interval sub-study database(http://physionet.org) comprising thirty subjects. Ten of the subjectsreceived encainide, ten received flecainide, and ten receivedmoricizine, with less than 7% premature ventricular beats. FIG. 8A showsthe MSE results for the pre-treatment (PRE) and the on-therapy (POST) RRtime series from a representative subject of those who receivedencainide. FIG. 9A shows the MSE results for the PRE and POST RR timeseries from a representative subject of those receiving flecainide. FIG.10A shows the MSE results for the PRE and POST RR time series from arepresentative subject of those receiving moricizine.

The complexity index (CI) is defined as the area under the MSE curve.FIGS. 8B, 9B and 10B show the complexity indexes before (PRE) and after(POST) the treatment onset with the drugs encainide, flecainide andmoricizine, respectively. In all cases but two in each group oftreatment the complexity of the system decreased after the initiation ofthe therapy. Significant differences (p<0.05) between the complexityindexes before and after treatment onset were obtained from theone-tailed paired Wilcoxon test for the results presented in FIGS. 8, 9,and 10. The null hypothesis is that the complexity indexes forpre-treatment (PRE) and on-therapy (POST) are drawn from populationswith the same mean and standard deviation.

In another embodiment, the MSE method can be used to test for anincrease in physiologic complexity as a predictor of beneficialtherapeutic effects for non-pharmaceutical therapy. For example,recently, Collins and colleagues (See A. Priplata, J. Niemi, J. Harry,L. Lipsitz, and J. Collins, “Vibrating insoles and balance control inelderly people,” Lancet, Vol. 362, pp. 1123-1124, Oct. 4, 2003,available at www.thelancet.com, which is incorporated herein byreference) showed that the application of subsensory noise to the soleof the feet of young and elderly subjects enhances sensory and motorfunction, possibly via a stochastic resonance type of mechanism. Theapplication of noise was associated with a reduction in the amount ofpostural sway variability in the elderly group.

Based on the concept that healthy systems are the most complex, theinventors applied the MSE method to the analysis of the 30-second swaytime series derived from 15 young and 12 elderly healthy subjects underbaseline conditions and with subsensory noise. These datasets areavailable at the open-access PhysioNet website(hht://physionet.org/physiobank/nesfdb). Young subjects did 20 trials:10 with subsensory noise and 10 without. Elderly subjects did 10 trials:5 with subsensory noise and 5 without. FIG. 11A presents the MSE resultsfor the young subjects, while FIG. 11B presents the MSE results for theelderly subjects. Symbols represent mean sample entropy values for allsubjects, all trials, and error bars represent standard errors.

As FIG. 11B shows, the complexity significantly (p<0.05) increases withthe application of subsensory noise to the soles of the feet in theelderly group. These results are consistent with traditional stabilogrammeasures that indicate an increase of postural stability with subsensorynoise. Furthermore, the MSE analysis predicts a beneficial therapeuticintervention leads to an increase of dynamical complexity

Parameter Values for MSE Computations

For a discussion on the optimal selection of m and r parameters, and theconfidence intervals of sample entropy estimates, see D. E. Lake et al.,American Journal of Physiology, 283, R789 (2002), which is incorporatedherein by reference. For m=2 and r=0.15, the discrepancies between themean values of the sample entropy for simulated time series and thenumerically calculated values are less than 1% for both 1/f and whitenoises. This result suggests that for most practical applications theerror bars associated with the computation of sample entropy values arelikely smaller than the error bars related to experimental sources andalso to inter- and intra-subject variability.

Effect of Noise, Outliers, and Sample Frequency in MSE Computation

For a time series sampled at frequency f, the temporal location of theactual heartbeat can be identified only up to the accuracy of Δ=1/f.Each data point of a coarse-grained heartbeat interval time series is anaverage of consecutive differences. For example: y₁ ^(τ)=(RR₁+ . . .+RR_(τ−1))/τ=[(t₂−t₁)+ . . . +(t_(τ)−t_(τ−1))]=(t_(τ)−t₁)/τ. Therefore,the accuracy of averaged heartbeat intervals of coarse-grained timeseries is Δ/τ, i.e., the accuracy increases with scale.

Sample entropy is underestimated for finite sample frequency values.However, the discrepancy between the value of the sample entropycalculated for a time series sampled at a finite frequency and the valueof the sample entropy (SE) corresponding to the limit (lim_(Δ→0) SE)decreases with scale. For analysis on small time scales it may beimportant to consider a correction of this effect. However, theconclusions presented herein are not altered by the value of samplefrequency.

MSE Analysis of Discrete Time Series

The MSE approach can be applied to discrete time series, such as DNAsequences. Consider an uncorrelated random variable “X” with alphabetΘ={0, 1}. Both symbols occur with probability 1/2. All possibledifferent 2-component sequences built from the binary series are: 00,01, 10 and 11. Therefore, the alphabet of the coarse-grained time seriescorresponding to scale 2 is: Θ₂={0, 1/2, 1}. The probabilitiesassociated with the occurrence of the different values are: 1/4, 1/2 and1/4, respectively.

Assuming that the r value used to calculate the sample entropy is 0.5,only the distance between the coarse-grained values 0 and 1 (and notbetween values 0 and 1/2, and between 1/2 and 1) is higher than r.Therefore, the probability of distinguishing two data points randomlychosen from the coarse-grained time series, Pr (|x_(a)−x_(b)|>r), is“p(0)×p(1)=1/4×1/4=1/16=0.0625.”

Similarly, there are eight different 3-component sequences that can bebuilt from the original binary series: 000, 001, 010, 100, 110, 011, 101and 111. Consequently, the alphabet of the coarse-grained time seriescorresponding to scale 3 is: Θ₃={0, 1/3, 2/3, 1} and the probabilitiesassociated with the occurrence of each value are 1/8, 3/8, 3/8, 1/8,respectively. For r=0.5, only the distances between the coarse-graineddata points 0 and 2/3, 1/3 and 1, and 0 and 1 are higher than r.Therefore, Pr(|x_(a)−x_(b)|>r)=p(0)×p(2/3)+p(1/3)×p(1)+p(0)×p(1)=0.1094.

FIG. 12 illustrates the probability of distinguishing any two datapoints randomly chosen from the coarse-grained time series of a binarydiscrete time series, having an r value of 0.5. Note that theprobability of distinguishing two data points of the coarse-grained timeseries increases from scale 2 to scale 3. As a consequence, the sampleentropy also increases, contrary to the results obtained from theanalytic derivation of the sample entropy values for white noise timeseries. This artifact, which affects discrete time series, is due to thefact that the size of the alphabet of the coarse-grained time seriesincreases with scale.

In general, for scale n, the alphabet set is: Θ_(n)={i/n} with 0≦i≦n,and the corresponding probability set, {p(i/n)} is generated by theexpression: n!/(2 ^(n)×i!(n−i)!), 0≦i≦n. The value of P_(r)(|x_(a)−x_(b)|>r) is calculated by the equation:

${P_{r}\left( {{{x_{a} - x_{b}}} > r} \right)} = {\sum\limits_{j = 0}^{N - 1}{{p\left( {j\text{/}n} \right)}{\sum\limits_{i = 1}^{n}{p\left( {{\mathbb{i}}\text{/}n} \right)}}}}$where, i=N+j+1 if n=2N (even scales), and i=N+j if n=2N−1 (odd scales).

FIG. 12 shows how the probability varies with the scale factor, and anattenuated oscillation, which as a consequence also shows up on the MSEoutput curve for the same time series. The period of this oscillationdepends only on the r value.

To overcome this artifact, one approach is to select the scales forwhich the entropy values are either local minima or maxima of the MSEcurve. This procedure was adopted to calculate the complexity of codingversus non-coding DNA sequences (see FIG. 14).

An alternative approach is to map the original discrete time series to acontinuous time series, for example, by counting the number of symbols(1's or 0's) in nonoverlapping windows of length 2^(n). Since thisprocedure is not a one-to-one mapping, some information encoded on theoriginal time series is lost. Therefore, relatively long time series arerequired. As discussed below with reference to FIG. 13, this procedurewas adopted to calculate the complexity of binary time series derivedfrom a computer executable file and a computer data file.

Application of MSE to Artificial and Biological Coding

In another embodiment of the present invention, the MSE approach isapplied to binary sequences of artificial and biological codes, aimed atquantifying the complexity of coding and non-coding deoxyribonucleicacid (DNA) sequences. In all cells, from microbes to mammals, proteinsare responsible for most structural, catalytic and regulatory functions.Therefore, the number of protein-coding genes that an organism makes useof could be an indicator of its degree of complexity. However, severalobservations contradict this reasoning.

Large regions of DNA, which in humans account for about 97% of the totalgenome, do not code for proteins and were previously thought to have norelevant purpose. These regions have been referred to “junk” DNA or gene“deserts.” However, these non-coding sequences are starting to attractincreasing attention as more recent studies suggest that they may havean important role in regulation of transcription, DNA replication,chromosomal structure, pairing, and condensation.

Detrended fluctuation analyses have revealed that non-coding sequencescontained long-range correlations and possessed structural similaritiesto natural languages, suggesting that these sequences could in factcarry important biological information. In contrast, coding sequenceshave been found to be more like a computer data file than a naturallanguage.

The biological implications of the presence of long-range correlationsin non-coding sequences, their origin, and nature are still beingdebated. Audit et al. have investigated the relation between long-rangecorrelations and the structure and dynamics of nucleosomes (see B. Auditet al., Phys. Rev. Lett. 86, 2471, (2001); and B. Audit et al., J. Mol.Biol. 316, 903 (2002), which are both incorporated herein by reference).Their results suggest that long-range correlations extending from 10 to200 base pair (bp) are related to the mechanisms underlying the wrappingof DNA in the nucleosomal structure.

Gene regulatory elements or enhancers are types of functional sequencesthat reside in non-coding regions. Until recently, enhancers werethought to be located near the genes that they regulate. However,subsequent in vivo studies have demonstrated that enhancers and thegenes to which they are functionally linked may be separated by morethan thousands of bases. These results reinforce earlier evidence thatthe non-coding sequences contain biological information and furthersupport the notion that, there are several “layers” of information ingenomic DNA.

The MSE approach, as described above, can be applied to analyze thecomplexity of both coding and non-coding DNA sequences of humanchromosomes. However, because of possible parallelisms betweenartificial and biological codes, first, two examples of artificiallanguage sequences are considered. The first example is a compiledversion of the LINUX Operating System (an executable computer program),and the second example is a compressed non-executable computer datafile. Both can be analyzed as binary sequences.

Although both files contain useful information, the structure of thatinformation is very different. The sequence derived from the executableprogram exhibits long-range correlations, while the sequence derivedfrom the data file does not. These results indicate that the computerprogram, which executes a series of instructions and likely containsseveral loops running inside each other, possesses a hierarchicalstructure, in contrast to the computer data file. Therefore, the formeris expected to be more complex than the latter.

When applied to discrete sequences (binary codes), the MSE resultspresent a typical artifact due to the dependence of the entropy valueson the size of the sequence alphabet. To overcome this artifact, oneapproach is to map the original time series to a continuous time series,for example, by counting the number of symbols (1's or 0's) innonoverlapping windows of length 2^(n). Since this procedure is not aone-to-one mapping, some information encoded on the original time seriesis lost. Therefore relative long time series are required. Thisprocedure was adopting in calculating the complexity of binary timeseries derived from a computer executable file and a computer data file.

The results of an MSE analysis for binary time series from a computerexecutable file and a computer data file are illustrated in FIG. 13.First, for scale 1, the sequence derived from the data file is assigneda higher entropy value than the sequence derived from the executableprogram. Second, between scales 2 and 6, the sample entropy measure doesnot separate the coarse-grained sequences of the two files.Additionally, for scales larger than scale 6, the highest entropy valuesare assigned to coarse-grained sequences derived from the executableprogram file. Furthermore, the difference between the sample entropyvalues assigned to coarse-grained sequences of the executable file andthe computer data file increases with scale factor. These resultsindicate that the structure of the executable file is more complex thanthe structure of the data file. Of note, conventional (single scale)entropy algorithms applied to sequences of artificial languages fail tomeaningfully quantify their overall complexity.

An alternative approach to overcome the artifact on the MSE curves ofdiscrete time series is to select the scales for which the entropyvalues are either local minima or maxima of the MSE curve. Thisprocedure was adopted in calculating the complexity of coding versusnoncoding DNA sequences as illustrated in FIG. 14.

The DNA building units are four nucleotides. Two of them contain apurine base (adenine (A) or guanine (G)), and the other two contain apyrimidine base (cytosine (C) or thymine (T)). There are many ways ofmapping the DNA sequences to a numerical sequence that take intoconsideration different properties of the DNA sequences. For thisapplication, the purine-pyrimidine rule was considered. Given theoriginal DNA sequence, bases A and C are mapped to number 1, and bases Cand T are mapped to number −1.

The results of an MSE analysis for coding and noncoding human DNAsequences on GenBank database, available as of June 2004 and, 30 binaryrandom time series are illustrated in FIG. 14, according to anembodiment of the present invention. For scales larger than scale 7,sample entropy values for non-coding sequences are higher than forcoding sequences. Consistently, for all scales but the first one, thelowest sample entropy values are assigned to coarse-grained time seriesderived from uncorrelated white noise mapped to a binary sequence. Theseresults show that the structure of non-coding sequences is more complexthan the structure of coding sequences analyzed here.

These findings suggest a parallelism between executable computerprograms and non-coding sequences, and data storing files and codingsequences. They also support the view that non-coding sequences containimportant biological information. Biological complexity and phenotypevariations, and therefore the MSE approach of the present invention,should relate not only to proteins, which are the main effectors ofcellular activity, but also to the organizational structure of thecontrol mechanisms responsible for the networking and integration ofgene activity.

Time Asymmetry Analysis of Physiologic Complexity

As discussed above, time asymmetry is another dynamical measurement thatcan be applied to quantify different aspects of physiologic complexityand information content. Living systems are subject to mass, energy,entropy, and information fluxes across their boundaries. These opensystems function in conditions far from equilibrium. They utilize energyto evolve to more hierarchically ordered structural configurations andless entropic states in comparison with the surrounding environment.Loss of self-organizing capability can be a marker of pathology. Inextreme cases presaging death, a state approaching maximum equilibriumis reached.

Time asymmetry (also referred to herein as “time irreversibility”) isdefined as a lack of invariance of the statistical properties under theoperation of temporal inversion. Time irreversibility is a fundamentalproperty of nonlinear, non-equilibrium systems. Surprisingly, relativelylittle work has been published on practical implementation of timereversibility to biologic time series.

It can be shown that: 1) time irreversibility is greatest for healthyphysiologic systems, which exhibit the most complex dynamics; and 2)time irreversibility decreases with aging or pathology, providing amarker of loss of functionality and adaptability. Therefore,quantitative measurements of time irreversibility can be of basic andpractical importance.

A number of computational measures of time irreversibility have beenproposed and applied to physiologic and physical time series. Theseconventional measures, however, are all single scale-based. In contrast,complex biologic systems typically exhibit spatio-temporal structuresover a wide range of scales. Therefore, the present invention provides atime irreversibility measure that incorporates information from multiplescales. The present invention can be applied to both physical andphysiologic time series.

Consider the time series X={x₁, x₂, . . . , x_(N)} and let “τ” be aninteger number representing the time lag between two data points. Thistime series is processed to compute multiple coarse-grained time seriesaccording to the equation y_(τ)(i)=(x_(τ+i)−x_(i))/τ with i≦N−τ.

A measure of temporal irreversibility is defined by the equation:

${{a(\tau)} = \frac{\int_{0}^{\infty}{\left\lbrack {{{\rho\left( y_{\tau} \right)}\ln\;{\rho\left( y_{\tau} \right)}} - {{\rho\left( {- y_{\tau}} \right)}\ln\;{\rho\left( {- y_{\tau}} \right)}}} \right\rbrack^{2}\ {\mathbb{d}y_{\tau}}}}{\int_{- \infty}^{\infty}{{\rho\left( y_{\tau} \right)}\ln\;{\rho\left( y_{\tau} \right)}\ {\mathbb{d}y_{\tau}}}}},$where ρ(y_(τ)) represents the probability distribution function of thecoarse-grained time series for scale τ. The time series is reversible ifand only if a(τ)=0.

For biologic systems, it is not only important to quantify the degree ofirreversibility of a time series but also to know which time seriesrepresents the “forward” direction and which is time reversed. a(τ) doesnot provide that information. Thus the following quantity is definedinstead:

${A(\tau)} = \frac{\int_{0}^{\infty}{\left\lbrack {{{\rho\left( y_{\tau} \right)}\ln\;{\rho\left( y_{\tau} \right)}} - {{\rho\left( {- y_{\tau}} \right)}\ln\;{\rho\left( {- y_{\tau}} \right)}}} \right\rbrack\ {\mathbb{d}y_{\tau}}}}{\int_{- \infty}^{\infty}{{\rho\left( y_{\tau} \right)}\ln\;{\rho\left( y_{\tau} \right)}\ {\mathbb{d}y_{\tau}}}}$If A(τ)>0 then for scale τ the time series is irreversible. However, ifA(τ)=0, the time series may or may not be irreversible for scale τ.

Real-world signals, such as heart rate time series, are sampled at afinite frequency, in which case y_(τ), is a discrete variable. For theanalysis of these signals the following equation provides an estimatorof A(τ):

${{\hat{A}(\tau)} = {\frac{\sum\limits_{y_{\tau} > 0}{{\Pr\left( y_{\tau} \right)}{\ln\left\lbrack {\Pr\left( y_{\tau} \right)} \right\rbrack}}}{\sum\limits_{y_{\tau}}{{\Pr\left( y_{\tau} \right)}{\ln\left\lbrack {\Pr\left( y_{\tau} \right)} \right\rbrack}}} - \frac{\sum\limits_{y_{\tau} < 0}{{\Pr\left( y_{\tau} \right)}{\ln\left\lbrack {\Pr\left( y_{\tau} \right)} \right\rbrack}}}{\sum\limits_{y_{\tau}}{{\Pr\left( y_{\tau} \right)}{\ln\left\lbrack {\Pr\left( y_{\tau} \right)} \right\rbrack}}}}},$where Pr(y_(τ)) denotes the probability of the value y_(τ).

In an embodiment, the multiscale asymmetry index (A_(I)) is computedfrom the following equation:

$A_{I} = {\sum\limits_{\tau = 1}^{L}{{\hat{A}(\tau)}.}}$

Referring to FIG. 15, flowchart 1500 represents the general operationalflow of an embodiment of the present invention. More specifically,flowchart 1500 shows an example of a control flow for quantifyingphysiologic complexity from time irreversibility measurements.

The control flow of flowchart 1500 begins at step 1501 and passesimmediately to step 1503. At step 1503, a series of physiologic data isgathered from non-invasive and/or invasive measurements taken from asubject. For example, data can be taken from a twenty-four hourcontinuous ECG Holter monitor recording, and used to derive an RRinterval time series.

At step 1506, the physiologic time series data is processed to computemultiple coarse-grained time series as described above. At step 1509,the value of Â(τ) is calculated for each coarse-grained time series. Atstep 1512, the multiscale asymmetry index (A_(I)) is computed as thearea under the asymmetry curve Â(τ).

At step 1515, the A_(I) metric is compared to a threshold parameter. Thethreshold parameter is an A_(I) measurement produced from a physiologictime series representative of a normal or healthy subject. The computedA_(I) (from step 1515) and the threshold A_(I) are compared to analyzethe relative degree of temporal irreversibility of the two time series.

If the A_(I) is higher for the threshold A_(I) than for the computedA_(I), control passes to step 1518, and loss of temporal irreversibilityis detected. Otherwise, control passes to step 1521, and no loss oftemporal irreversibility is detected. If the A_(I) is higher for thecomputed A_(I) than for the threshold A_(I), an increase in complexityis determined. Afterwards, the control flow ends as indicated at step1595.

Referring back to step 1512, note that the A_(I) metric corresponds tothe area between the solid and dotted curves shown in FIGS. 16A-16D.

In an embodiment, the time asymmetry approach can be used to quantifythe effects of drug and non-pharmacologic intervention. As such,interventions that enhance system time asymmetry (as detected at step1521) are associated with therapeutic effects, and interventions thatdegrade system time asymmetry (as detected at step 1518) are associatedwith adverse effects.

FIG. 16 illustrates the multiscale time irreversibility (asymmetry)analysis of the cardiac interbeat interval sequences derived fromtwenty-four hour Holter monitor recordings of representative subjects.The scale factor is referenced to heartbeat number. FIG. 16 presents theA_(I) values for groups of 26 healthy young subjects (FIG. 16A), 46healthy elderly subjects (FIG. 16B), 43 patients with congestive heartfailure (FIG. 16C) and 9 subjects with atrial fibrillation (FIG. 16D).

The data used for the time asymmetry analysis was obtained from anopen-access database that is available at:http://www.physionet.org/physiobank/database/. As can be inferred fromFIGS. 16A-16E, the time asymmetry index A_(I) (i.e., the area betweenthe two curves) is higher for the healthy young subjects than for bothhealthy elderly subjects and the subjects with pathology. Furthermore,the lowest A_(I) values are assigned to the subjects with pathology.Note that, conventional (single scale-based) time asymmetry measures donot yield consistent differences.

Consistent results have been obtained from another study conducted withtwenty-six healthy young subjects (A_(I)=0.54±0.20, mean±standarddeviation), forty-six healthy elderly subjects (A_(I)=0.37±0.22),forty-three CHF subjects (A_(I)=0.09±0.29), and nine subjects withatrial fibrillation (A_(I)=0.00±0.02). Differences between groups aresignificant (p<0.005, t-test), with the exception of the two pathologicstates (CHF vs. atrial fibrillation). Cardiac interbeat interval timeseries obtained during the sleeping period yield comparable results.Therefore, nonstationarities due to physical activity do not account forthese asymmetry properties.

The results are compatible with the general concept that timeirreversibility degrades with aging and disease over multiple timescales. Of note, both highly irregular heartbeat time series (such asthose from subjects with atrial fibrillation) and less variable, moreregular time series (such as those from heart failure subjects) tend tobe more time symmetric than time series derived from healthy subjects.

The inventors have tested the hypothesis that cardiac interbeat intervaltime series of healthy subjects have greater time asymmetry thanartificial time series generated by algorithms designed to model heartrate dynamics. To test the hypothesis, the time asymmetry approach hasbeen applied to a database of fifty time series that is available fromthe PhysioNet/Computers in Cardiology Challenge 2002: RR Interval TimeSeries Modeling. As predicted, the asymmetry index was determined to behigher for physiologic time series than for the synthetic ones. Thisfinding indicates that the proposed models do not fully account for thenon-equilibrium properties of the control mechanisms that regulate heartrate under healthy conditions.

Multiscale time irreversibility analysis of time series providesinformation not extractable from conventional methods, including entropymeasures and spectral techniques. This approach can be useful for boththe development of realistic models of physiologic control and forbedside diagnostics, since time asymmetry is a fundamental property ofhealthy, far from equilibrium systems.

Information-Based Similarity Analysis of Physiologic Complexity

As discussed above, information-based similarity (IBS) is anotherdynamical measurement that can be applied to quantify different aspectsof physiologic complexity and information content. Complex physiologicsignals can carry unique dynamical signatures that are related to theirunderlying mechanisms. The information-based similarity approach isbased on rank order statistics of symbolic sequences to investigate theprofile of different types of physiologic dynamics. This approachprovides a quantitative metric to define distances among the symbolicsequences.

The information-based similarity approach can be applied to heart ratefluctuations (the output of a central physiologic control system). Thisapproach robustly discriminates patterns generated from healthy andpathologic states, as well as aging. Furthermore, an increasedrandomness is observed in the heartbeat time series with physiologicaging and pathologic states, and also nonrandom patterns have beenuncovered in the ventricular response to atrial fibrillation.

As discussed above, physiologic systems generate complex fluctuations intheir output signals that reflect the underlying dynamics. Therefore,finding and analyzing hidden dynamical structures of these signals areof both basic and clinical interest. According to embodiments of thepresent invention, the information-based similarity approach detects andquantifies such temporal structures in the human heart rate time seriesusing tools from statistical linguistics.

Human cardiac dynamics are driven by the complex nonlinear interactionsof two competing forces: sympathetic stimulation which increases heartrate and parasympathetic stimulation which decreases heart rate. Forthis type of intrinsically noisy system, it may be useful to simplifythe dynamics via mapping the output to binary sequences, where theincrease and decrease of the interbeat intervals are denoted by 1 and 0,respectively. The resulting binary sequence retains important featuresof the dynamics generated by the underlying control system, but istractable enough to be analyzed as a symbolic sequence.

Referring to FIG. 17, flowchart 1700 represents the general operationalflow of an embodiment of the present invention. More specifically,flowchart 1700 shows an example of a control flow for quantifyingphysiologic complexity from information-based similarity measurements.

The control flow of flowchart 1700 begins at step 1701 and passesimmediately to step 1703. At step 1703, two time series of physiologicdata are gathered from non-invasive and/or invasive measurements takenfrom the same subject or from different subjects depending on the aimsof the study. If the study is aimed at characterizing changes in thesystem's dynamics over time or accessing the effects of an intervention,the two time series are gathered from measurements taken from the samesubject at two different time points. In contrast, the time series aregathered from measurements taken from different subjects, when the studyis aimed at comparing the outputs generated by different systems. Thedata can, for example, be taken from two readings of a twenty-four hourcontinuous ECG Holter monitor recording, and used to derive two RRinterval time series.

At step 1706, each original time series is mapped to a binary timeseries. In the case of heartbeat time series each pair of successiveinterbeat intervals are mapped to the symbols 0 or 1, according to theequation:

$I_{n} = \left\{ {\begin{matrix}{0,\mspace{14mu}{{{if}\mspace{14mu} x_{n}} \leq x_{n - 1}},} \\{1,\mspace{14mu}{{{if}\mspace{14mu} x_{n}} > x_{n - 1}},}\end{matrix},} \right.$where x_(i) is the i^(th) interbeat interval. In this case, the symbols0 and 1 represent an increase and a decrease in heart rate,respectively.

In an embodiment, “m+1” successive intervals are mapped to a binarysequence of length m, which herein is referred to as an “m-bit word.”Each m-bit word “w_(k)”, therefore, represents a unique pattern offluctuations in a given time series.

At step 1709, a collection of m-bit words (x_(i), x_(i+1), . . .x_(i+m−1)) with 1≦i≦N−m+1 are produced. It is plausible that theoccurrence of these m-bit words reflects the underlying dynamics of theoriginal time series since different types of dynamics produce differentdistributions of these m-bit words.

Step 1706 and step 1709 can be further explained with reference to FIG.18, which illustrates a mapping procedure for 8-bit words from part of atwo hour heartbeat time series. The symbol 0 represents a decreasebetween a pair of successive interbeat intervals, and the symbol 1represents an increase between a pair of successive interbeat intervals.As shown, nine successive intervals are mapped to a binary sequencerepresenting each 8-bit word. For example, the first word is shown as“11000110”, the second word is “10001100”, the third word is “00011001”,and so forth. As described in greater detail below, the occurrence ofthese 8-bit words reflects the underlying dynamics of the original timeseries.

In studies of natural languages, it has been observed that differentauthors have a preference for the words they use with higher frequency.To apply this concept to symbolic sequences mapped from the interbeatinterval time series, at step 1712, the occurrences of different wordsare counted, and at step 1715, the different words are sorted accordingto descending frequency. The resulting rank-frequency distribution,therefore, represents the statistical hierarchy of symbolic words of theoriginal time series. For example, the first ranked word corresponds toone type of fluctuation that is the most frequent pattern in the timeseries. In contrast, the last ranked word defines the most unlikelypattern in the time series.

Steps 1712 and 1715 can be further explained with reference to FIGS. 19and 20. FIG. 19 illustrates a probability distribution of every 8-bitword from the time series analyzed in FIG. 18. The word index rangesfrom 0 to 2^(m−1) for m-bit words. For the example analyzed in FIG. 19,the length m is eight, and there is a total of 256 possible words.

FIG. 20 illustrates a rank ordered probability plotted on a log-logscale. The linear regime (for rank ≦50) is reminiscent of Zipf's law fornatural languages. Referring back to step 1712 and step 1715, theoccurrence of the different 8-bit words (from FIG. 18) are counted inFIG. 19, and the words are sorted according to descending frequency inFIG. 20.

After a rank-frequency distribution (see FIG. 20) has been produced forboth time series from step 1703, control passes to step 1718. At step1718, a measurement of similarity between the two signals is defined byplotting the rank number of each m-bit word in the first time seriesagainst that of the second time series. FIG. 21 illustrates a rank ordercomparison of two cardiac interbeat interval time series from the samesubject. If two time series are similar in their rank order of thewords, the scattered points would be located near the diagonal line.Therefore, the average deviation of these scattered points away from thediagonal line is a measure of the “distance” between these two timeseries. Greater distance indicates less similarity and vice versa.

In an embodiment, the likelihood of each word is incorporated in thefollowing definition of a weighted distance “D_(m)” between two symbolicsequences, S₁ and S₂:

${D_{m}\left( {S_{1}S_{2}} \right)} = \frac{\sum\limits_{k = 1}^{2^{m}}\;{{{{R_{1}\left( w_{k} \right)} - {R_{2}\left( w_{k} \right)}}}{p_{1}\left( w_{k} \right)}{p_{2}\left( w_{k\;} \right)}}}{\left( {2^{m} - 1} \right){\sum\limits_{k = 1}^{2^{m}}\;{{p_{1}\left( w_{k} \right)}{p_{2}\left( w_{k} \right)}}}}$

The expressions “p₁(w_(k))” and “R₁(w_(k))” represent probability andrank of a specific word “w_(k)” in time series S₁. Similarly,“p₂(w_(k))” and “R₂(w_(k))” stand for probability and rank of the samem-bit word in time series S₂. The absolute difference of ranks ismultiplied by the normalized probabilities as a weighted sum and dividedby the value 2^(m−1) to keep the D_(m) value in the same range of [0,1]. After the similarity measurement has been computed, the control flowends as indicated at step 1795.

As discussed in greater detail below, it can be shown that the distancemeasurement (D_(m)) can be applied to identify unique dynamical patternsassociated with an individual. This similarity measurement can also beapplied to identify characteristic patterns that describe the dynamicalstructures of different physiologic or pathologic states. As a healthysystem changes, with disease and aging, quantifiable changes can bedetected in the dynamical patterns related to the degradation of theintegrative control systems.

In an embodiment, where time series were gathered from a group ofprototypically healthy subjects (group A) and from a group of patientsbefore (group B) and after an intervention (group C), the distancesbetween all different pairs of signals are calculated. Next, theintergroup distances are calculated. The intergroup distance betweengroups A and B is defined as the average distance between all pairs ofsignals where one is from group A and the other from group B. Aphylogenetic tree is then generated according to the distances betweendifferent groups. The further apart from the group of prototypicallyhealthy subjects, the less complex will be a time series.

In an embodiment, the information-based similarity approach can be usedto quantify the effects of drug and non-pharmacologic interventions. Assuch, interventions that enhance system complexity are associated withtherapeutic effects, and that interventions that degrade systemcomplexity are associated with adverse effects.

The information-based similarity measurement has been tested on subjectdata located in databases available at the website www.physionet.org/.(See A. L. Goldberger et al., Circulation 101, E215 (2000), which isincorporated herein by reference). The databases include fortyostensibly healthy subjects with subgroups of young (including tenfemales and ten males, average 25.9 years) and elderly (including tenfemales and ten males, average 74.5 years). The databases also include agroup of forty-three subjects with severe congestive heart failure(including fifteen females and twenty-eight males, average 55.5 years),and a group of nine subjects with atrial fibrillation. All subjects inthe healthy and atrial fibrillation groups have two hour recordings. TheCHF group has longer data sets (i.e., 16-to-24 hours for each subject).Only an analysis for the case m=8 is presented herein. However, similarresults have been obtained for the cases m=4-to-12.

First, the information-based similarity measurements was applied to thedatabase data to examine whether the distance for subsets of the timeseries from the same subject is closer than that for the time seriesfrom different subjects under similar physiologic states. Each subject'stime series were divided into two subsets to measure the distancebetween these two subsets.

The distance (e.g., D_(m)) was calculated between each pair of subjectswho belong to the same group. The “intrasubject distance” representsaverage distances measured between two subset time series from the samesubject. The “intragroup distance” represents average distances betweentwo different subjects from the same group.

For the group of healthy young subjects, the intrasubject distance is0.056±0.050 (mean±standard deviation), and the intragroup distance is0.161±0.106. For the group of healthy elderly subjects, the intrasubjectdistance is 0.077±0.052, and the intersubject distance is 0.209±0.110.For the group of subject with congestive heart failure, the intrasubjectdistance is 0.053±0.047, and the intersubject distance is 0.100±0.062.Finally for the group of subjects with atrial fibrillation, theintrasubject distance is 0.046±0.015, and the intersubject distance is0.045±0.012. These results show that the intrasubject distances areindeed smaller than the intragroup distances. The small intrasubjectdistances indicate that there are unique dynamical patterns associatedwith each individual at small time scales. The only exception is for theatrial fibrillation group. It is difficult to distinguish one subjecthaving atrial fibrillation from another based on the rank orderdistance. This result is consistent with previous studies showing that,on small time scales (≦200 s), heart rate fluctuations of subjectshaving atrial fibrillation do not exhibit consistent structures.

Measuring the average distance between subjects across different groups,it can be seen that distances between subjects across groups aretypically greater than distances between subjects within a group. Thisresult supports the notion that there are dynamical patterns fordifferent physiologic or pathologic states. However, there is overlapamong groups. The intergroup distances are calculated among all groupsfrom the databases as well as a group of 100 artificial time series ofuncorrelated noise (white noise group).

The method for constructing phylogenetic trees is a useful tool topresent the above results since the algorithm arranges different groupson a branching tree to best fit the pairwise distance measurements. FIG.22 shows the result of a rooted tree for the case of m=8. The tree hasbeen generated according to the distances between five groups, namelyhealthy young subjects, healthy elderly subjects, CHF subjects, atrialfibrillation subjects, and white noise indicating a simulateduncorrelated random time series. The distance between any two groups isthe summation of the horizontal lengths along the shortest path on thetree that connects them. For example, the distance is 0.211 betweenhealthy young and healthy elderly groups.

The structure of the tree is consistent with the underlying physiology:the farther down the branch the more complex the dynamics are. Thegroups are arranged in the following order (from bottom to top as shownin FIG. 22). First, the time series from the healthy young grouprepresents dynamical fluctuations of a highly complex integrativecontrol system. Second, the healthy elderly group represents a slightdeviation from the “optimal” youthful state, possibly due to thedecoupling (or dropout) of components in the integrative control system.Third, severe damage to the control system is represented by the CHFgroup. These individuals have profound abnormalities in cardiac functionassociated with pathologic alterations in both the sympathetic and theparasympathetic control mechanisms that regulate beat-to-beatvariability. Fourth, the atrial fibrillation group is an example of apathologic state in which there appears to be very limited externalinput on the heartbeat control system. Finally, the artificial whitenoise group represents the extreme case in that only noise and no signalis present.

A further application of the rank order distance concept is to quantifythe degree of nonrandomness. To this end, a surrogate time series isgenerated by random shuffling of the original time series. Randomshuffling of the data yields exactly the same distribution of theoriginal interbeat intervals sequence, but destroys their sequentialordering. The distance (i.e., D_(m)) between an interbeat interval timeseries and its randomized surrogate provides an index of thenonrandomness of the time series.

FIG. 23 illustrates a heartbeat interval time series from a healthysubject showing complex variability. In contrast, a time series from aCHF subject (as illustrated in FIG. 24) shows less variability. FIG. 25shows a rank order comparison of the time series in FIG. 23. As can beseen for healthy subjects, the rank map between each original signal andits randomized surrogate shows prominent scatter. The measurednonrandomness is 0.31.

FIG. 26 shows a rank order comparison of the time series in FIG. 24. Incontrast to FIG. 25, heart rate dynamics with CHF show rank maps withrelatively narrow distributions indicating that fluctuations in CHF arecloser to random (nonrandomness index=0.10).

Next, the information-based similarity measurement is applied tocalculate nonrandomness distances that correspond to different wordlengths “m” ranging from two to twelve. FIG. 27 shows the result form=8. For healthy and CHF subjects, there are significant differences(p<10⁻⁴) in this nonrandomness index over the entire range of “m”studied. However, the nonrandomness distance of the healthy young groupis only significantly higher than that of the healthy elderly group atthe scale m=3 (p<0.05), suggesting a preservation of most of thenonrandom features of heart rate dynamics with physiologic aging.Subjects with atrial fibrillation also show significantly higher valuesof the nonrandomness index than white noise over the range of 5≦m≦9(p<10⁻⁴). Therefore, even on small time scales, the information-basedsimilarity measurements can effectively discriminate certain data setsof the atrial fibrillation group from white noise, whereas conventionalmethods have not been successful in this regard.

Another attractive feature of rank order statistics is that the methodis useful in examining the details of the underlying dynamics. Forexample, the nonrandomness test indicates a significant differencebetween atrial fibrillation and uncorrelated noise. The rank numbers ofthe “words” that contribute to this difference from white noise can befurther analyzed. The assumption is that if a word dramatically changesits rank after randomization (shuffling), the fluctuations mapped bythis word may not be random and could contain relevant structuralinformation. After systemically reviewing all atrial fibrillationrecordings, the words that are significantly different from randomsequences, occurring in a subset of these subjects, are given as(00100100), (00110001), (00101000), and (01000100). This findingsuggests hidden structural organization in the short-term variation ofthe ventricular rhythm in atrial fibrillation. These sequences needfurther systematic analysis, in conjunction with information fromintracardiac electrophysiologic studies, to elucidate the mechanism ofthe ventricular response to atrial fibrillation in different settings.

Thus, the information-based similarity approach introduces aquantitative metric to define distances among symbolic sequences. Inapplication to the heart rate time series, this approach provides newquantitative information that is not measured by conventional heart ratevariability techniques. This method can be easily adapted to otherphysiologic and physical time series provided that a meaningful mappingto symbolic sequences can be obtained. Finally, this linguistic-typemethod is potentially useful because of its ability to take into accountboth macroscopic structures and the microscopic details of the dynamics.

In another embodiment, the invention is used to assess the stability ofthe output of non-biologic networks. For example, the invention can beused to assess the stability of the output of the global Internet, awide area network (WAN), a local area network (LAN), a Web server, othertelecommunications networks, electricity flow in a power grid, as wellas systems for managing air traffic flow, automotive traffic flow,shipping traffic in busy sea ports, rail traffic flow, and the like. Insuch environments, a loss of complexity in the output of the system maybe a marker of a breakdown of network stability and possibly of animpending catastrophic failure. Thus, while the invention is describedabove primarily in biologic environments, the invention has wideapplication in non-biologic environments.

For example, in the environment of the global Internet, the fluctuationsof network traffic under normal (“healthy”) conditions should exhibithigher levels of complexity as measured by MSE compared with those underpathologic conditions related to virus attack or other intrinsic orextrinsic disruptions.

Exemplary Computer System Implementation

FIGS. 1-27 provide an exemplary environment for describing variousexemplary embodiments of the present invention. It should be understoodthat embodiments of the present invention could be implemented inhardware, firmware, software, or a combination thereof. In such anembodiment, portions of the various components and steps would beimplemented in hardware, firmware, and/or software to perform thefunctions of the present invention. That is, the same piece of hardware,firmware, or module of software could perform one or more of theillustrated blocks (i.e., components or steps).

The present invention can be implemented in one or more computer systemscapable of carrying out the functionality described herein. Referring toFIG. 28, an example computer system 2800 useful in implementing thepresent invention is shown. Various embodiments of the invention aredescribed in terms of this example computer system 2800. After readingthis description, it will become apparent to one skilled in the relevantart(s) how to implement the invention using other computer systemsand/or computer architectures.

The computer system 2800 includes one or more processors, such asprocessor 2804. The processor 2804 is connected to a communicationsinfrastructure 2806 (e.g., a communications bus, crossover bar, ornetwork).

Computer system 2800 can include a display interface 2802 that forwardsgraphics, text, and other data from the communications infrastructure2806 (or from a frame buffer not shown) for display on the display unit2830.

Computer system 2800 also includes a main memory 2808, preferably randomaccess memory (RAM), and can also include a secondary memory 2810. Thesecondary memory 2810 can include, for example, a hard disk drive 2812and/or a removable storage drive 2814, representing a floppy disk drive,a magnetic tape drive, an optical disk drive, etc. The removable storagedrive 2814 reads from and/or writes to a removable storage unit 2818 ina well-known manner. Removable storage unit 2818, represents a floppydisk, magnetic tape, optical disk, etc., which is read by and written toremovable storage drive 2814. As will be appreciated, the removablestorage unit 2818 includes a computer usable storage medium havingstored therein computer software (e.g., programs or other instructions)and/or data.

In alternative embodiments, secondary memory 2810 can include othersimilar means for allowing computer software and/or data to be loadedinto computer system 2800. Such means can include, for example, aremovable storage unit 2822 and an interface 2820. Examples of such caninclude a program cartridge and cartridge interface (such as that foundin video game devices), a removable memory chip (such as an EPROM, orPROM) and associated socket, and other removable storage units 2822 andinterfaces 2820, which allow software and data to be transferred fromthe removable storage unit 2822 to computer system 2800.

Computer system 2800 can also include a communications interface 2824.Communications interface 2824 allows software and data to be transferredbetween computer system 2800 and external devices. Examples ofcommunications interface 2824 can include a modem, a network interface(such as an Ethernet card), a communications port, a PCMCIA slot andcard, etc. Software and data transferred via communications interface2824 are in the form of signals 2828 which can be electronic,electromagnetic, optical, or other signals capable of being received bycommunications interface 2824. These signals 2828 are provided tocommunications interface 2824 via a communications path (i.e., channel)2826. Communications path 2826 carries signals 2828 and can beimplemented using wire or cable, fiber optics, a phone line, a cellularphone link, an RF link, free-space optics, and/or other communicationschannels.

In this document, the terms “computer program medium” and “computerusable medium” are used to generally refer to media such as removablestorage unit 2818, removable storage unit 2822, a hard disk installed inhard disk drive 2812, and signals 2828. These computer program productsare means for providing software to computer system 2800. The inventionis directed to such computer program products.

Computer programs (also called computer control logic or computerreadable program code) are stored in main memory 2808 and/or secondarymemory 2810. Computer programs can also be received via communicationsinterface 2824. Such computer programs, when executed, enable thecomputer system 2800 to implement the present invention as discussedherein. In particular, the computer programs, when executed, enable theprocessor 2804 to implement the processes of the present invention, suchas the various steps of methods 100, 200, 1600, and 2200, for example,described above. Accordingly, such computer programs representcontrollers of the computer system 2800.

In an embodiment where the invention is implemented using software, thesoftware can be stored in a computer program product and loaded intocomputer system 2800 using removable storage drive 2814, hard drive2812, interface 2820, or communications interface 2824. The controllogic (software), when executed by the processor 2804, causes theprocessor 2804 to perform the functions of the invention as describedherein.

In another embodiment, the invention is implemented primarily inhardware using, for example, hardware components such as applicationspecific integrated circuits (ASICs). Implementation of the hardwarestate machine so as to perform the functions described herein will beapparent to one skilled in the relevant art(s).

In yet another embodiment, the invention is implemented using acombination of both hardware and software.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art (including the contents of thedocuments cited and incorporated by reference herein), readily modifyand/or adapt for various applications such specific embodiments, withoutundue experimentation, without departing from the general concept of thepresent invention. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed embodiments, based on the teaching and guidance presentedherein. It is to be understood that the phraseology or terminologyherein is for the purpose of description and not of limitation, suchthat the terminology or phraseology of the present specification is tobe interpreted by the skilled artisan in light of the teachings andguidance presented herein, in combination with the knowledge of oneskilled in the art.

It should also be understood the each of the documents and Internetwebsites referenced above are incorporated herein by reference as ifreproduced in full below.

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofexample, and not limitation. It will be apparent to one skilled in therelevant art(s) that various changes in form and detail can be madetherein without departing from the spirit and scope of the invention.Thus, the present invention should not be limited by any of theabove-described exemplary embodiments, but should be defined only inaccordance with the following claims and their equivalents.

1. A method of assessing stability of a network based on a series ofdata associated with the network, comprising: analyzing the series ofdata to produce a measure of complexity, wherein the analyzing includes:computing a multiple coarse-grained time series from the series of data,calculating a sample entropy measure from the multiple coarse-grain timeseries, and plotting the sample entropy measure as a function of a scalefactor to thereby produce a multiscale sample entropy curve; comparingthe complexity measure to a control, wherein the comparing includes:comparing the multiscale sample entropy curve to a threshold curve tothereby detect loss, gain, or consistency in complexity; and assessingthe stability of the network based on the comparison of the complexitymeasure to the control, wherein the analyzing, comparing and assessingare performed by one or more processors.
 2. The method of claim 1,wherein the comparing step further comprises: comparing the multiscalesample entropy curve to a threshold curve, wherein the threshold curveis taken at a prior time.
 3. The method of claim 1, wherein thecomparing step further comprises: comparing the multiscale sampleentropy curve to a threshold curve, wherein the threshold curve is takenfrom a different network.
 4. The method of claim 1, wherein theanalyzing step further comprises: analyzing the series of data, whereinthe series of data is from a network selected from the group consistingof a global Internet, a wide area network, a local area network, a Webserver, a telecommunications network, a power grid, air traffic flow,automotive traffic flow, shipping traffic flow, and rail traffic flow.5. The method of claim 1, wherein the assessing step further comprises:indicating a positive effect of a change to the network when a gain incomplexity is detected.
 6. The method of claim 1, wherein the assessingstep further comprises: indicating a negative effect of a change to thenetwork when a loss in complexity is detected.
 7. A computer programproduct comprising a non-transitory computer useable medium havingcomputer readable program code functions embedded in the medium forcausing a computer to assess stability of a network based on a series ofdata associated with the network, comprising: a first computer readableprogram code function that causes the computer to analyze the series ofdata to produce a measure of complexity, including causing the computerto: process the series of data to produce multiple coarse-grained timeseries; calculate a degree of irreversibility of each coarse-grainedtime series; and sum the degrees of irreversibility for thecoarse-grained time series to compute a multiscale time asymmetry index;a second computer readable program code function that causes thecomputer to compare the complexity measure to a control; and a thirdcomputer readable program code function that causes the computer toassess the stability of the network based on the comparison of thecomplexity measure to the control.
 8. The computer program product ofclaim 7, wherein the second computer readable program code functioncomprises: computer readable program code function to compare thecomplexity measure to a control, wherein the control is selected fromthe group consisting of a complexity measure taken at a prior time, acomplexity measure taken from a different network, and a predeterminedthreshold value.
 9. The computer program product of claim 7, wherein thethird computer readable program code function indicates a positiveeffect of a change to the network when a gain in complexity is detectedand indicates a negative effect of the change when a loss in complexityis detected.
 10. The computer program product of claim 7, wherein thesecond computer readable program code function compares the complexitymeasure to a control, wherein the multiscale time asymmetry index is thecomplexity measure and the control is a threshold index.
 11. Acomputer-based system to assess stability of a network based on a seriesof data associated with the network, comprising: first means foranalyzing the series of data to produce a measure of complexity, whereinthe first means for analyzing includes: means for classifying each pairof successive intervals from the series into one of two statesrepresenting a decrease or an increase between intervals; means formapping the two states to binary symbols to produce a plurality ofbinary words, wherein each word has a length m and is shifted one datapoint with respect to an adjacent word, wherein each m-bit wordrepresents a unique pattern of fluctuation in the series; and means forproducing a rank-frequency distribution from the plurality of m-bitwords; second means for comparing the complexity measure to a control;and third means for assessing the stability of the network based on thecomparison of the complexity measure to the control.
 12. Thecomputer-based system of claim 11, wherein the second means furthercomprises: means to compare the complexity measure to a control, whereinthe control is selected from the group consisting of a complexitymeasure taken at a prior time, a complexity measure taken from adifferent network, and a predetermined threshold value.
 13. Thecomputer-based system of claim 11, wherein the third means indicates apositive effect of a change to the network when a gain in complexity isdetected and indicates a negative effect of the change when a loss incomplexity is detected.
 14. The computer-based system of claim 11,wherein the second means compares the rank-frequency distribution to athreshold rank-frequency distribution for a second series of data tothereby detect loss, gain, or consistency in complexity.